Non-canonical functions of autophagy proteins

自噬蛋白的非典型功能

基本信息

批准号：
10163773
负责人：
DOUGLAS R GREEN
金额：
$ 44.88万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163773
关键词：
1-Phosphatidylinositol 3-Kinase Affect Age Alpha Particles Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Apoptotic Autophagocytosis Autophagosome Bacteria Biochemical Biochemistry Biological Biology Brain Cell membrane Cell physiology Cell-Free System Cells Complex Defect Degenerative Disorder Dendritic Cells Digestion Disease Elements Endocytosis Endosomes Epithelial Cells Event Generations Health Immune response Immune system Inflammation Inflammatory Inflammatory Response Investigation Ligase Link Lipids Lysosomes Membrane Microbe Microglia Modality Molecular Myelogenous Myeloid Cells Natural Immunity Nematoda Neurodegenerative Disorders Nutrient Outcome Pathway interactions Phagocytes Phagocytosis Phagosomes Phosphotransferases Physiological Process Protein Family Proteins Recruitment Activity Recycling Role Surface Therapeutic autoinflammatory base experimental study fly fungus in vivo lupus-like macrophage neuroinflammation novel pathogen receptor receptor recycling recruit response tool

项目摘要

The ancient processes of phagocytosis and autophagy co-evolved as mechanisms of nutrient acquisition and pathogen defense, and under some circumstances their functional machineries intersect. This is the case for LC3-associated phagocytosis (LAP), a process in which some components of the autophagy pathway are recruited to the phagosome to lipidate LC3 molecules on this single membrane. LAP and canonical autophagy are distinct at the molecular, cellular, and organismal levels. Since we discovered this process eleven years ago, LAP has been implicated in immune responses to a variety of bacteria and fungi, and in several other physiological and disease settings. We have also identified a related, but distinct process of LC3-associated endocytosis (LANDO), which functions in the endocytosis of b-amyloid involved in Alzheimer’s Disease (AD). This application will explore the mechanisms of LAP and LANDO and their roles in myeloid responses in AD. We have chosen an AD model in which to interrogate the impact of LAP/LANDO defects in myeloid cells in vivo, and the core biochemistry of LAP in cell-free systems. We envision three aims of this project. 1. What are the mechanisms of LAP that distinguish it from conventional autophagy? Because LAP and autophagy share several molecular features, it is important to understand how LAP and autophagy are distinct at a molecular level. Here, we will explore the formation of the class 3 PI-3-kinase complex, unique to LAP, and how its activity recruits the ligase complex (common to LAP and autophagy) in a manner that is distinct from that of autophagy. 2. How does LANDO differ from conventional autophagy and LAP, and how does it influence cellular processes? We have identified a process, LANDO, distinct from LAP and autophagy, which nevertheless uses several of the proteins involved in each. We have found that this process is required for the recycling of several surface receptors to the plasma membrane following their internalization, even in non-phagocytic cells. We will interrogate LAP and autophagy proteins for their roles in LANDO and explore how these and other proteins known to be involved in receptor recycling influence cellular functions, including engulfment and inflammatory responses. 3. How do LAP and LANDO influence a model of Alzheimer’s Disease? Here, we will focus on the roles of LAP and LANDO in the clearance of amyloid by myeloid cells in the brain, and the consequences of defective LAP and/or LANDO for neuro-inflammation and degeneration. While studies of the decline of autophagic responses with age have been linked to disease, ours will be the first to do so in the context of these processes. LAP, LANDO, and autophagy share several molecular features but are distinct, and our studies proposed will reveal how these distinctions influence health and disease at the molecular, cellular, and organismal levels.

吞噬作用和自噬的古老过程作为营养获取和自噬的机制共同进化。病原体的防御，在某些情况下它们的功能机制是交叉的。 LC3 相关吞噬作用 (LAP)，自噬途径的某些组成部分被激活的过程被招募到吞噬体以脂质化该单膜上的 LC3 分子和典型的自噬。自从我们发现这个过程十一年以来，它们在分子、细胞和生物水平上都有所不同。以前，LAP 与多种细菌和真菌的免疫反应有关，并且与其他几种免疫反应有关。我们还发现了 LC3 相关的相关但独特的过程。内吞作用 (LANDO)，在参与阿尔茨海默病 (AD) 的 β-淀粉样蛋白内吞作用中发挥作用。本申请将探讨 LAP 和 LANDO 的机制及其在 AD 骨髓反应中的作用。我们选择了一个 AD 模型来探究 LAP/LANDO 缺陷对骨髓细胞的影响体内，以及 LAP 在无细胞系统中的核心生物化学我们设想该项目的三个目标 1. 什么。 LAP 与传统自噬的区别是什么？自噬具有多个分子特征，了解 LAP 和自噬的区别非常重要在这里，我们将探索 LAP 独有的 3 类 PI-3-激酶复合物的形成，以及它的活性如何以独特的方式招募连接酶复合物（LAP 和自噬常见）与自噬的区别 2. LANDO 与传统自噬和 LAP 有何不同？它会影响细胞过程吗？我们已经确定了一个不同于 LAP 的过程 LANDO 和自噬，尽管如此，我们发现这个过程使用了几种参与其中的蛋白质。是几种表面受体内化后再循环到质膜所必需的，即使在非吞噬细胞中，我们也会探究 LAP 和自噬蛋白在 LANDO 和探索这些和其他已知参与受体循环的蛋白质如何影响细胞功能，包括吞噬和炎症反应 3. LAP 和 LANDO 如何影响模型。阿尔茨海默病？在这里，我们将重点关注 LAP 和 LANDO 在淀粉样蛋白清除中的作用大脑中的骨髓细胞，以及 LAP 和/或 LANDO 缺陷对神经炎症和疾病的影响虽然自噬反应随年龄下降的研究已与疾病相关，我们将是第一个在 LAP、LANDO 和自噬过程中这样做的人。分子特征但又截然不同，我们提出的研究将揭示这些区别如何影响健康以及分子、细胞和生物水平上的疾病。